Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

210 Applying Pharmacogenomics in Therapeutics
to determine an association regarding efficacy of the antidepressants include the
following: G-protein coupled receptors, tryptophan hydroxylase (TPH) I, monoamine
oxidase, dopamine receptor, noradrenergic receptor, nitric oxide, angiotensinconverting
enzyme, interleukin-1β, stress hormone system, and phosphodiesterase.
A recent meta-analysis concluded that evidence suggests that 5-HTTLPR, 5-HT1A,
5-HT2A, TPH1, and brain-derived neurotropic factor may modulate antidepressant
response, despite the presence of some heterogeneity across the studies. 5
SCHIZOPHRENIA
Drug Efficacy
A substantial number of trials have been conducted to predict the efficacy of antipsychotics
in the treatment of schizophrenia with both the first- and second-generation
antipsychotics. Studies have supported the importance of both the dopaminergic and
serotonergic systems in mediating efficacy, but less is known about the substantiated
roles of other neurotransmitter systems at this time. 5 These studies are difficult to
complete, however, as there are differing sample and illness characteristics, antipsychotic
medication types, treatment durations, adherence, adjuvant treatments, and
outcome phenotypes.
Adverse Effects
The C allele of rs381929 polymorphism (−759C/T) has been consistently associated
with weight gain in patients taking antipsychotic drugs. A meta-analysis of the association
between this polymorphism and weight gain concluded that the −759T allele
is associated with less weight gain. 25 For clinical practice, if testing is available,
antipsychotic drugs that have been demonstrated to stimulate weight gain should be
avoided in carriers of the protective T allele. 25
Clozapine-induced agranulocytosis (CIA) has a poorly understood mechanism.
The relative rarity of CIA significantly limits the collection of large samples required
to conduct robust genomic samples needed to determine the predictability of the
adverse event. Several mechanisms have been studied, and one resulted in a commercially
available product, clozapine metabolite-induced neutrophil toxicity and
immune system mediation.
From 2002 to 2007, PGxHealth (pgxhealth.com) completed a GWAS that demonstrated
that HLA-DQB1 6672G>C was a risk for CIA, and a 16.9-fold increased risk
for carriers of this marker. In 2007, a commercial test was marketed to determine
whether a patient was “lower risk” or “higher risk” for CIA. The problem of the test
was the 21.5% sensitivity, which has been a limiting factor in its application in clinical
settings. 26,27
Another association that has been demonstrated in a small trial is the reduction
on dihydronicotinamide riboside quinone oxidoreductase 2 mRNA levels seen
in patients with CIA compared with controls. The complexity of possible genetic
mechanisms in CIA may be very challenging, but adding to the complexity is the
additional need for studies with varying ethnicities and environmental factors, which
may also play a role in the rate of development of CIA. 28,29